Is IGLL1 p.Pro142= (c.426G>A) pathogenic?

IGLL1 p.Pro142= (c.426G>A) is classified Uncertain significance in IGLL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-15). Very rare (popmax 0.00667%, amr); Associated with agammaglobulinemia 2, autosomal recessive.

What condition is associated with IGLL1 p.Pro142= (c.426G>A)?

IGLL1 p.Pro142= (c.426G>A) is associated with agammaglobulinemia 2, autosomal recessive (ClinVar).

How common is IGLL1 p.Pro142= (c.426G>A) in the general population?

IGLL1 p.Pro142= (c.426G>A) is very rare (popmax 0.00667%, amr) (gnomAD).

IGLL1 p.Pro142=

c.426G>A · rs560833188 · VCV1445521

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Conditions

agammaglobulinemia 2, autosomal recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.55	acceptor gain · deltas
Pangolin	Δ0.33	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -9.2	GERP -3.4
Overall
CADD	18.05	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% Admixed American · 4/60,008 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00118% 19/1,613,872 alleles · very rare exomes 15/1,461,648 · genomes 4/152,224 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	15,002
South Asian	0.0022%	45,536
Finnishnot grpmax-eligible	0.00156%	64,036
European (non-Finnish)	0.00102%	98,319

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: IGLL1
Protein: p.Pro142=
Coding: c.426G>A
MANE Select: NM_020070
dbSNP: rs560833188
Type: single nucleotide variant
Location: chr22:23573482 (GRCh38)
Gene constraint: LOEUF 1.844 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 75.19 · 3 PDB
Residue 142: a β-strand; the ig-like c1-type domain; the 'c region' region; a UniProt-annotated variant site (in agm2)

Full IGLL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

agammaglobulinemia 2, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

IGLL1 p.Pro142Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
IGLL1 p.Ala12Val Uncertain significance ★★ ⚠ same condition
IGLL1 p.Ala174Ser Uncertain significance ★★ ⚠ same condition
IGLL1 p.Arg23His Uncertain significance ★★ ⚠ same condition
IGLL1 p.Arg2Lys Uncertain significance ★★ ⚠ same condition
IGLL1 p.Arg40Cys Uncertain significance ★★ ⚠ same condition
IGLL1 p.Arg48Gly Uncertain significance ★★ ⚠ same condition
IGLL1 p.Arg60Gln Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/igll1-p-pro142 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown